When a histocompatible donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) provides a highly successful modality with which to correct congenital disorders of hematopoiesis. The major barrier preventing more widespread use of this approach is the availability of a matched donor, especially for underserved minorities and patients with rapidly progressive disease. During the past five years, we and others have made significant progress in overcoming this barrier by attempting to develop strategies that will facilitate haploidentical HSCT. We hypothesized that manipulation of donor T-cells to induce long lasting unresponsiveness to recipient alloantigens would increase the donor pool while ameliorating HSCT toxicities associated with alloreactivity. In our phase I trial of ex vivo induction of donor T-cell anergy to recipient alloantigens, we demonstrated the feasibility of this approach and have successfully performed haploidentical donor HSCT in 2 children with congenital disorders of hematopoiesis. In order for greater numbers of patients with congenital disorders of hematopoiesis to be offered this modality earlier, their disease course, we must improve the therapeutic index of HSCT. To achieve this goal, we must weight the we-established and considerable short-term and long-term toxicities of HSCT from allogeneic matched and haploidentical donors against the immediate life- expectancy and quality of life of the patient with a chronic disease. For these patients, neither radically increasing acute morbidity or mortality nor substituting one chronic disease for another would be acceptable outcomes. The therapeutic index would be significantly improved if: 1) alloreactivity unique to each donor: recipient pair could be specifically eliminated; 2) short and long term side-effects of chemoradiotherapeutic myeloablative therapy could be reduced or prevented; and 3) immunocompetence could be rapidly restored after HSCT. As long as these goals are not met, the risk: benefit ratio will continue to favor the more benign forms of palliative care rather than the risky but curative approach of HSCT. To achieve these ends, three specific aims are proposed. First, we will modify our methodology such that we will be able to induce and assess alloantigen specific T-cell anergy in donor T- cells to perform HSCT for patients with congenital disorders of hematopoiesis. Second, we will apply this improved methodology in clinical translational trials with the goals of making donors available for all suitable patients, reducing the rate of clinically significant acute and/or chronic GVHD and improving the rate and degree of immunologic reconstitution. Third, we will attempt to reduce or ameliorate the need for high dose chemoradiotherapy by exploring the feasibility of generating T- cells or monoclonal antibodies directed against hematopoietic stem and progenitor cell antigens which might be able to ablate hematopoiesis. Although these aims are ambitious, we expect to make considerable progress during this funding period. Realization of these goals may make it possible to use a near universal donor poor to correct congenital diseases of hematopoiesis by HSCT without the debilitating acute and chronic toxicities which accompany allogenicity, immunocompetence, and regimen related end-organ damage.